Download PDF

Clinical Trial Results:
GLOOCOSE Study - A randomised controlled trial of the sulfonylurea Gliclazide and the DPP4 inhibitor Linagliptin on the frequency of hypoglycaemia among patients with Type 2 Diabetes and chronic kidney disease (CKD) stage 3b and 4.

Summary
EudraCT number	2015-002309-12
Trial protocol	GB
Global end of trial date	08 Jun 2019

Results information
Results version number	v1(current)
This version publication date	16 Jun 2020
First version publication date	16 Jun 2020
Other versions
Summary report(s)	GLOOCOSE Study Final Report

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

16HH3133

ISRCTN number

ISRCTN17462005

US NCT number

WHO universal trial number (UTN)

Other trial identifiers

Andrew Frankel: Chief Investigator, REC: 15/LO/1548

Sponsor organisation name

Imperial College London, Joint Research Compliance Office (JRCO)

Sponsor organisation address

Room 221, Medical School Building, St Marys Campus, Norfolk Place, London, United Kingdom, W2 1PG

Public contact

Becky Ward, Imperial College London, Joint Research Compliance Office (JRCO), +44 020 7594 9480, jrco@ic.ac.uk

Scientific contact

Becky Ward, Imperial College London, Joint Research Compliance Office (JRCO), +44 020 7594 9459, becky.ward@imperial.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

08 Jun 2019

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Jun 2019

Global end of trial reached?

Yes

Global end of trial date

08 Jun 2019

Was the trial ended prematurely?

Main objective of the trial

1. To assess whether patients with type 2 diabetes and moderate to severe kidney disease have less hypoglycaemia when taking Linagliptin instead of Gliclazide 2. To assess whether these same patients have decreased glycaemic variability when taking Linagliptin compared to Gliclazide 3. To assess whether Linagliptin has any other advantages over Gliclazide by examining effects on serum and urine biomarkers associated with declining kidney function 4. To assess whether study participants are more satisfied on Linagliptin or Gliclazide

Protection of trial subjects

Regular review of patient's diabetes control, especially pertaining to frequency of hypoglycaemic and hyperglycaemic episodes and symptoms. A member of the research team would meet with each study patient within a month of study end to go over his or her CGM results, and advise if their current diabetic treatment was satisfactory, or if it needed to be changed. A letter detailing their CGM results and the research team’s recommendations would also be sent to the patients and their GPs.

Background therapy

All subjects taking Metformin, Pioglitazone and/or basal insulin at the time of recruitment into the study, and as part of their routine diabetic management, will continue on their pre-randomisation dose/s during the 8 weeks following randomisation. The dose will vary between subjects, the licenced oral dose for Metformin ranges being between 500 mg once a day to 1 gm twice a day, with the dose adjustments according to the NICE guidelines. The licenced oral dose for Pioglitazone ranges from 15 mg to 45 mg daily.

Evidence for comparator

Actual start date of recruitment

04 May 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 23

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

See below for study eligibility criteria. Eligibility screening was performed using clinic data held on the diabetic and renal patients attending Imperial College NHS Healthcare trust and relevant community clinics.

Screening details

The study inclusion criteria were: 1. Type 2 diabetes mellitus 2. Age between 21 - 80 years inclusive 3. eGFR of 15 - 45 ml/min/1.73 m2 4. HbA1c < 75 mmol/mol (< 9%) 5. Taking Gliclazide with or without Metformin, Pioglitazone and/or basal insulin 6. Stable diabetic control in last 2 months 7. Understands adequate verbal and written English

Period 1 title

Overall trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

No intervention

Arm description

Patients randomised to continue on their usual dose of Gliclazide (ranging from 40 mg once daily to a maximum dose of 320mg daily in divided doses)

Arm type

No intervention

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Linagliptin

Arm description

Patients randomised to stop Gliclazide and switch to Linagliptin

Arm type

Active comparator

Investigational medicinal product name

Linagliptin

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Linagliptin 5mg once daily

Number of subjects in period 1 ^[1]	No intervention	Linagliptin
Started	10	9
Completed	10	7
Not completed	0	2
Adverse event, non-fatal	-	1
CGM technical failure	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Difficult recruitment resulted in less patients recruited compared to initial recruitment aim. Although 23 were consented to the trial, 4 were withdrawn from the study prior to randomisation for failure to comply with research procedures.

Baseline characteristics

Top of page

Reporting group title

No intervention

Reporting group description

Patients randomised to continue on their usual dose of Gliclazide (ranging from 40 mg once daily to a maximum dose of 320mg daily in divided doses)

Reporting group title

Linagliptin

Reporting group description

Patients randomised to stop Gliclazide and switch to Linagliptin

Reporting group values	No intervention	Linagliptin	Total
Number of subjects	10	9	19
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
median (full range (min-max))	72 (50 to 76)	71 (57 to 79)	-
Gender categorical
Units: Subjects
Female	2	0	2
Male	8	9	17
Ethnicity
Units: Subjects
Caucasian	6	6	12
Afrocaribbean	1	0	1
Asian	2	3	5
Other/Mixed	1	0	1
Weight
Units: kilogram(s)
median (full range (min-max))	97.5 (60.8 to 116.6)	80.2 (64.8 to 103.8)	-
Body mass index (BMI)
Units: kilogram(s)/square meter
median (full range (min-max))	33.1 (25.7 to 39.5)	29.4 (22.4 to 33.8)	-
Blood pressure
For systolic blood pressure values only
Units: mmHg
median (full range (min-max))	141 (99 to 173)	134 (94 to 153)	-
Duration of diabetes
Units: years
median (full range (min-max))	13 (6 to 23)	14 (3 to 30)	-
HbA1c
Glycated haemoglobin (mmol/mol)
Units: mmol/mol
median (full range (min-max))	55 (39 to 62)	52 (33 to 64)	-
Fasting capillary blood glucose
Units: mmol/L
median (full range (min-max))	7.5 (5.6 to 10.3)	6.5 (4.7 to 10.9)	-
Estimated Glomerular Filtration Rate eGFR MDRD
Units: ml/min/1.73m2
median (full range (min-max))	37 (20 to 45)	32 (26 to 44)	-
Urine albumin creatinine ratio (UACR)
Units: mg/mmol
median (full range (min-max))	35 (0 to 72)	6 (1 to 257)	-
Urine protein creatinine ratio (UPCR)
Units: mg/mmol
median (full range (min-max))	58 (0 to 136)	16 (0 to 339)	-

End points

Top of page

Reporting group title

No intervention

Reporting group description

Patients randomised to continue on their usual dose of Gliclazide (ranging from 40 mg once daily to a maximum dose of 320mg daily in divided doses)

Reporting group title

Linagliptin

Reporting group description

Patients randomised to stop Gliclazide and switch to Linagliptin

Primary: Change in outcome measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Top of page

End point title

Change in outcome measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

End point description

As above

End point type

Primary

End point timeframe

Study visits take place over 11 weeks, and patients randomised to either continue their usual Gliclazide or switch to Linagliptin for 8 weeks

End point values	No intervention	Linagliptin
Number of subjects analysed	10 ^[1]	7
Units: As per outcomes
median (full range (min-max))
Change in hypoglycaemic frequency	-1 (-8 to 16)	0 (-6 to 0)
Change in total time spent in hypoglycaemia	0 (-4 to 9)	0 (-5 to 0)
Change in mean CGM glucose	0.1 (-1.1 to 1.1)	1.5 (-0.4 to 6.8)
Change in estimated CGM HbA1c	0 (-8 to 7)	10 (-2 to 47)
Change in time spent in normoglycemia	-3.2 (-12.9 to 6.1)	-12 (-64 to 10.4)
Change in Percentage Coefficient of Variation	-0.7 (-12.1 to 12.9)	-9.2 (-15.7 to 6.3)
Change in Standard Deviation	0 (-1 to 0.8)	-0.6 (-0.9 to 0.6)
Change in Continuous Overall Net Glycaemic Action	-0.3 (-0.8 to 0.7)	0 (-0.7 to 0.7)
Change in Mean Absolute Glucose	-0.2 (-0.4 to 0.5)	0.1 (-0.5 to 0.5)
Change in Mean of Daily Differences	-0.2 (-1.5 to 0.2)	-0.4 (-0.7 to 0.3)
Change in Mean Amplitude of Glucose Excursions	0.3 (-1.9 to 3.3)	-1.4 (-2.5 to 1.7)
Change in time spent in hyperglycaemia >10 mmol/L	2.6 (-5.3 to 13.7)	11.3 (-10.2 to 69.0)
Change in time spent in hyperglycaemia >13.9 mmol/	0.6 (-10.5 to 4.6)	0.8 (-2.7 to 61.9)
Change in Low Blood Glucose Index	0 (-0.7 to 2.1)	-0.2 (-2.3 to 0)
Change in High Blood Glucose Index	0.3 (-2.8 to 3)	1.7 (-1.6 to 22.8)
Change in serum MCP-1	-12.1 (-55.2 to 14.0)	-18.1 (-47.5 to 20.9)
Change in urine MCP-1	-15.9 (-363.5 to 10)	-7.3 (-123.8 to 154.4)
Change in urine MCP-1/creatinine ratio	-4.4 (-30.6 to 1.5)	3.4 (-1 to 6.1)
Change in serum TGF-B1	2.6 (-1.9 to 7.9)	2.6 (-0.3 to 6)
Change in urine TGF-B1	0 (-198.5 to 72.6)	0 (-88 to 1023.4)
Change in urine TGF-B1/creatinine ratio	0 (-39.7 to 5.3)	0 (-4.7 to 47.6)
Change in overall DTSQ score	0.5 (-6 to 4)	2 (-6 to 10)
Change in Question 2 DTSQ	0 (-3 to 1)	0 (-2 to 4)
Change in Question 3 DTSQ	0.5 (-1 to 1)	0 (-2 to 1)

Notes
[1] - Based on 9 patient samples for all CGM measures

Mann Whitney

Statistical analysis description

Non-parametric independent samples

Comparison groups

No intervention v Linagliptin

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.86

upper limit

1.86

Other pre-specified: Change in clinical measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Top of page

End point title

Change in clinical measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

End point description

End point type

Other pre-specified

End point timeframe

Study visits take place over 11 weeks, and patients randomised to either continue their usual Gliclazide or switch to Linagliptin for 8 weeks

End point values	No intervention	Linagliptin
Number of subjects analysed	10 ^[2]	7 ^[3]
Units: See each individual endpoint
median (full range (min-max))
Change in weight, kg	0.3 (-1.1 to 4.8)	-0.5 (-3.8 to 0.1)
Change in BMI, kg/m2	0.1 (-0.4 to 1.7)	-0.1 (-1.4 to 0)
Change in BP, mmHg	5 (-29 to 22)	3 (-19 to 33)
Change in HbA1c, mmol/mol	1.5 (-2.0 to 11.0)	8.0 (-2.0 to 18.0)
Change in fasting CBG, mmol/L	0.5 (-0.9 to 1.2)	2.6 (0.6 to 6.8)
Change in eGFR MDRD, ml/min/1.73m2	1.0 (-2.0 to 9.0)	-1.0 (-3.0 to 1.0)
Change in urine ACR, mg/mmol	3.1 (-19.1 to 130.2)	-0.3 (-9.4 to 9.4)
Change in urine PCR, mg/mmol	8.0 (-22.0 to 157.0)	-1.0 (-20.0 to 39.0)

Notes
[2] - Based on 9 patient samples for change in urine PCR
[3] - Based on 6 patient samples for change in urine ACR and urine PCR

Mann-Whitney test

Statistical analysis description

Non-parametric independent samples

Comparison groups

Linagliptin v No intervention

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.05

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.86

upper limit

1.86

Adverse events

Top of page

Timeframe for reporting adverse events

Until end of study recruitment period

Adverse event reporting additional description

Subjects will be asked at each study visit and scheduled phone call before and after study visit 3 to assess and record: a) Episodes of symptomatic hypoglycaemia b) Episodes of symptomatic hyperglycaemia c) General health to include any adverse reactions/adverse events

Assessment type

Systematic

Dictionary name

SNOMED CT

Dictionary version

Reporting group title

No intervention

Reporting group description

Patients randomised to continue on their usual dose of Gliclazide (ranging from 40 mg once daily to a maximum dose of 320mg daily in divided doses)

Reporting group title

Linagliptin

Reporting group description

Patients randomised to stop Gliclazide and switch to Linagliptin

Serious adverse events	No intervention	Linagliptin
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 10 (0.00%)	0 / 9 (0.00%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0

Frequency threshold for reporting non-serious adverse events: 1%

Non-serious adverse events	No intervention	Linagliptin
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)
Hepatobiliary disorders
Deranged LFTs
Additional description: Subject had deranged liver function tests (LFTs) that were investigated and followed up. Deranged LFTs was put down to a passed gallstone.
subjects affected / exposed	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

12 Jun 2017

The substantial amendments mainly pertained to broadening of the eligibility criteria and summarising the PIS length from 11 to 3 pages. The age limit of eligible study participants was extended to 21 to 80 years inclusive. The initial eligibility criteria stated that patients had to have type 2 diabetes of 10 years or more duration – this was removed, as duration of diabetes was not usually accurately coded or unavailable during searches, and also not considered to influence the study findings. The protocol was amended to include patients taking Gliclazide, either with or without Metformin, Pioglitazone and/or basal insulin. This change to the eligibility criteria intended to increase recruitment numbers while still allowing for comparison of study patients staying on their usual Gliclazide to those randomised to Linagliptin. The HbA1c cut off limit was raised from 65 mmol/mol (8%) to 75 mmol/mol (9%), with the aim of improving recruitment. Moreover, hypoglycaemia and glycaemic variability can still occur in patients at higher HbA1c levels. Duration of study recruitment was adjusted upward from two to three years, to allow for the slower recruitment rate.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The small number of patients may mean the study is underpowered to find statistical differences. Relatively short duration of randomisation to Linagliptin means maximum effect may not have been reached by 8 weeks, and limits the conclusions drawn.

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Clinical trials

Clinical Trial Results:
GLOOCOSE Study - A randomised controlled trial of the sulfonylurea Gliclazide and the DPP4 inhibitor Linagliptin on the frequency of hypoglycaemia among patients with Type 2 Diabetes and chronic kidney disease (CKD) stage 3b and 4.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in outcome measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Primary: Change in outcome measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Other pre-specified: Change in clinical measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Other pre-specified: Change in clinical measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: GLOOCOSE Study - A randomised controlled trial of the sulfonylurea Gliclazide and the DPP4 inhibitor Linagliptin on the frequency of hypoglycaemia among patients with Type 2 Diabetes and chronic kidney disease (CKD) stage 3b and 4.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in outcome measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Primary: Change in outcome measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Other pre-specified: Change in clinical measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Other pre-specified: Change in clinical measures post-randomisation (Visit 5) compared to pre-randomisation (Visit 2)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
GLOOCOSE Study - A randomised controlled trial of the sulfonylurea Gliclazide and the DPP4 inhibitor Linagliptin on the frequency of hypoglycaemia among patients with Type 2 Diabetes and chronic kidney disease (CKD) stage 3b and 4.